tbuckley/cabot-search huggingface dataset:
Abstract 3259: TAS3351 is a 4th-generation EGFR-TKI overcoming T790M and C797S-mediated resistance in NSCLC with EGFR common mutations
Authors: Hidefumi Kasuga, Yuki Kataoka, Fuyuki Yamamoto, Takashi Mizutani, Shingo Tsuji, Sakiho Tanaka, Shinji Mizuarai
Journal: Cancer Research (2022)

Abstract Background: Common mutations (exon 19 deletion; ex19del or L858R point mutation; L858R) of the epidermal growth factor receptor (EGFR) are found in patients with non-small cell lung cancer (NSCLC) and are sensitive to EGFR-tyrosine kinase inhibitors (TKIs), including osimertinib, a third-generation, irreversible EGFR-TKI. Although osimertinib is widely utilized as the standard of care in first-line therapy of NSCLC, resistance inevitably occurs during the treatment. Among EGFR-dependent/on-target resistant mechanisms of osimertinib, the C797S mutation is reported to emerge as the most frequent alteration. The cysteine residue at position 797 of EGFR is covalently bound with osimertinib, and its alteration to serine causes an inability to form a covalent bond, making osimertinib resistant to NSCLC with a C797S mutation. While first-generation, reversible EGFR-TKIs (gefitinib and erlotinib) might be effective for patients with C797S mutation, the T790M mutation is reported to emerge in almost half of patients with EGFR common mutations during treatment with first-generation EGFR-TKIs. Here, we report TAS3351 as a novel, next-generation EGFR-TKI designed to overcome C797S and T790M-mediated resistance in NSCLC patients. Methods: The inhibitory potency of TAS3351 on cellular phospho-EGFR was analyzed by In-cell western assay. In addition, inhibition of cell viability in Ba/F3 cells transformed by human wild type or mutated EGFR, as well as in human NSCLC cell lines whose EGFR harbors common mutations, was tested. Anti-tumor activity of TAS3351 was evaluated in NIH/3T3-EGFR allograft models and human NSCLC xenograft models. Results: TAS3351 exhibited almost comparable inhibitory potency against cellular phosphorylation of EGFR harboring ex19del or L858R with or without C797S and/or T790M while sparing wild type EGFR activity. TAS3351 also showed similar trends in the cell viability assay for Ba/F3-EGFR cells and human NSCLC cell lines. Finally, TAS3351 demonstrated favorable anti-tumor activity in NIH/3T3 allografts transformed by human EGFR harboring ex19del/C797S/T790M. Conclusion: TAS3351 is a fourth-generation EGFR-TKI overcoming T790M and C797S-mediated resistance in NSCLC with common mutations. The present results support the clinical development of TAS3351 as monotherapy in NSCLC patients with EGFR mutations harboring C797S and/or T790M EGFR-TKI resistance mutations. Citation Format: Hidefumi Kasuga, Yuki Kataoka, Fuyuki Yamamoto, Takashi Mizutani, Shingo Tsuji, Sakiho Tanaka, Shinji Mizuarai. TAS3351 is a 4th-generation EGFR-TKI overcoming T790M and C797S-mediated resistance in NSCLC with EGFR common mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3259.
Abstract 1286: Oral administration of poly gamma glutamic acid significantly enhances the antitumor immune response of doxorubicin in a murine cancer model through regulating tumor microenvironment
Authors: Joungwoo Choi, Solmin Jung, Yena Oh, Jaepyeong Jang, Yeondong Cho, Do young Lee, Youngcheol Park, Kwangil Jeong
Journal: Cancer Research (2022)

Abstract Immunogenic cell death (ICD) is a type of cancer cell death triggered by certain chemotherapeutic drugs, oncolytic viruses, and other therapies. In particular, doxorubicin (DOX), one of the chemo-drugs, is well known to induce ICD, which involves the activation of the immune system against cancer in immunocompetent hosts. ICD comprises the release of damage-associated molecular patterns (DAMPs) from dying tumor cells that result in the activation of tumor-specific immune responses, thus eliciting long-term efficacy of anticancer drugs by combining direct cancer cell killing and antitumor immunity. However, the antitumor immunity can be achieved by overcoming the immunosuppressive tumor microenvironment (TME). Most current treatment strategies harnessing the tumor microenvironment focus on T cell-immune response, either by promoting activating signals or suppressing inhibitory ones.We here present a novel approach to cope with the inhibitory TME, combinatory treatment of DOX with poly gamma glutamic acid (γ-PGA). PGA, a safe edible biomaterial secreted by B. subtillis, has been evaluated in the clinical trials with the patients diagnosed as cervical intraepithelial neoplasia 1 (CIN 1). From the study using murine cancer models, including MC38, we found the combinatory treatment with γ-PGA restored the downregulation of NK cell activity caused by DOX, enhanced ICD and T cell responses, and reduced proinflammatory cytokines in the tumor tissues. Taken together, co-administration of γ-PGA exhibited synergistic anti-cancer effects by favoring the immunosuppressive TME in the combinatory treatment with conventional chemo-drugs. Citation Format: Joungwoo Choi, Solmin Jung, Yena Oh, Jaepyeong Jang, Yeondong Cho, Do young Lee, Youngcheol Park, Kwangil Jeong. Oral administration of poly gamma glutamic acid significantly enhances the antitumor immune response of doxorubicin in a murine cancer model through regulating tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1286.
Abstract 1215: pVACsplice: Predicting neoantigens from tumor-specific alternative splicing events derived from cis-acting regulatory mutations using whole exome and RNA sequencing data
Authors: Megan M. Richters, Kelsy C. Cotto, Susanna Kiwala, Huiming Xia, Beatriz M. Carreno, Gavin P. Dunn, Antoni Ribas, Obi L. Griffith, Malachi Griffith
Journal: Cancer Research (2022)

Abstract Neoantigens are tumor-specific peptides on the cell surface that can be recognized by the adaptive immune system. Personalized immunotherapies, such as cancer vaccines, rely on neoantigen prediction to identify sequences that can activate T cells to recognize and destroy the tumor. The majority of cancer vaccine trials have utilized neoantigens derived from missense mutations and small insertions and deletions. However, other mutation types could contribute to the overall neoantigen landscape, such as aberrantly spliced transcripts arising from cis-acting regulatory mutations. In this study, we explore the potential immunogenicity of alternative splicing events by creating pVACsplice, a tool to expand the capability of pVACtools, a suite of tools for neoantigen prediction (http://www.pvactools.org). pVACsplice assembles alternative transcripts from tumor-specific splicing patterns, identifies sequence changes by comparison to a reference, and predicts neoantigens from the novel regions. To verify the accuracy of alternative transcript assembly, we ran pVACsplice with HCC1395 cell line samples and performed long-read sequencing to detect the transcripts in vitro. Matched whole exome sequencing and RNA sequencing datasets from glioblastoma, melanoma, and colorectal cancer cohorts will also be analyzed with pVACsplice to obtain binding affinity estimates. We will compare these results to neoantigen predictions from other mutation sources and across cancer types to discover the prevalence of immunogenic splicing events. Finally, we will perform immunogenicity testing with a set of high quality candidates to validate our predictions. We hope to increase the number of candidates for patients’ vaccines by adding this functionality to our standard neoantigen prediction workflow. This tool could help generate a more accurate portrait of the neoantigen landscape in tumors, and in turn, enhance responses to personalized immunotherapies. Citation Format: Megan M. Richters, Kelsy C. Cotto, Susanna Kiwala, Huiming Xia, Beatriz M. Carreno, Gavin P. Dunn, Antoni Ribas, Obi L. Griffith, Malachi Griffith. pVACsplice: Predicting neoantigens from tumor-specific alternative splicing events derived from cis-acting regulatory mutations using whole exome and RNA sequencing data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1215.
Abstract 5289: Activating p53 through MDM2 and WIP1 inhibition effectively inhibits tumors in liver adenocarcinoma
Authors: Chiao-Ping Chen, Chun-Nan Yeh, Yi-Ru Pan, Yu-Tien Hsiao, Chih-Hong Lo, Cai-Jhen Jhuang, Chiao-En Wu
Journal: Cancer Research (2022)

Abstract Intrahepatic cholangiocarcinoma (iCCA) is an adenocarcinoma arising from the intrahepatic bile duct and accounts for the second most cases of primary liver cancers after hepatocellular carcinoma. Lacking effective treatment leads to a poor prognosis for advanced iCCA so new targeted therapy is warranted. Impaired wild-type (WT) p53 tumor suppressor function by its negative regulators frequently occurs in iCCA. Therefore, restoration of WT p53 function by inhibiting its negative regulators is a therapeutic strategy being explored for cancer treatment. Both MDM2 inhibitor (MDM2i, RG7388) stabilizing p53 and WIP1 inhibitor (WIP1i, GSK2830371) increasing p53 phosphorylation lead to maximize p53 function. The combination of MDM2i/WIP1i has been reported in severe cancer types but no in vivo study has been done. In the current study, both liver adenocarcinoma cell lines, RBE and SK-Hep-1, were treated with the RG7388 alone and in combination with GSK2830371. Cell proliferation, clonogenicity, protein and mRNA expressions, and cell cycle distribution were performed to investigate the effect and mechanism of growth suppression. To evaluate the antitumor efficacy of RG7388 and GSK2830371 in vivo, xenografts with SK-Hep-1 cells were treated with combination therapy for two weeks in NOD-SCID mice. The combination of MDM2i and WIP1i significantly increased the growth inhibition, cytotoxic activity, increased p53 protein expression, and phosphorylation (Ser 15), leading to transactivation of downstream targets (p21 and MDM2). The in vivo test demonstrated that the combination treatment can significantly inhibit tumor growth. In this study, liver adenocarcinoma cell lines were inhibited by the combination via reactivation of p53 function evidenced by increased p53 expression, phosphorylation and its downstream targets. This efficacy was also validated by in vivo study. The current research provides a novel strategy for targeting the p53 pathway in liver adenocarcinoma. Citation Format: Chiao-Ping Chen, Chun-Nan Yeh, Yi-Ru Pan, Yu-Tien Hsiao, Chih-Hong Lo, Cai-Jhen Jhuang, Chiao-En Wu. Activating p53 through MDM2 and WIP1 inhibition effectively inhibits tumors in liver adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5289.
Accuracy of Rapid Antigen vs Reverse Transcriptase–Polymerase Chain Reaction Testing for SARS-CoV-2 Infection in College Athletes During Prevalence of the Omicron Variant
Authors: Jessica Tsao, Andrea L. Kussman, Cristina Costales, Benjamin A. Pinsky, Geoffrey D. Abrams, Calvin E. Hwang
Journal: JAMA Network Open (2022)
Abstract 6018: Expansion of mouse mammary epithelial stem cells in serum-free organoid growth medium
Authors: David Rowbotham, Samantha Rothwell, Allen C. Eaves, Sharon A. Louis, John Stingl
Journal: Cancer Research (2022)

Abstract Growing mammary epithelial cells as organoids in a three-dimensional (3D) cell culture environment represents a more physiological model system than conventional 2D adherent cell culture systems for studying many different aspects of mammary epithelial cell biology. We have developed MammoCult™ Organoid Growth Medium (Mouse), a serum- and phenol red-free medium for the long-term propagation of organoids from mouse mammary tissue. To initiate the cultures, mouse mammary glands are resected and enzymatically dissociated sequentially in Gentle Collagenase/Hyaluronidase, trypsin, and dispase/DNase I to generate a single-cell suspension, and 4.5 x 103 of the liberated cells are then embedded in Corning® Matrigel® and maintained in MammoCult™ Organoid Growth Medium (Mouse). Alternatively, freshly dissociated mammary cells can be expanded in adherent culture in EpiCult™ Plus Medium prior to seeding into Matrigel®. Approximately 8.4 ± 0.6% (mean ± SEM; n=10) of the freshly dissociated cells seeded in the Corning® Matrigel® will proliferate and generate organoids that are typically &amp;gt; 200 µm in diameter and have a highly branched morphology, although organoids with a cystic morphology are also observed. Immunostaining of these branched organoids reveals that they are composed of a polarized epithelium made up of keratin (K) 8-expressing luminal cells and K5/14-expressing basal cells (n=7). Organoids upregulate transcripts for caseins (Csn1s1, Csn2), whey acidic protein (Wap), and lactoferrin (Ltf) upon stimulation with prolactin, hydrocortisone, and insulin (n=4). These multilineage organoids can be established from multiple inbred mouse strains, including C57Bl6/J, FVB, BALB/c, and CD-1. Organoids can be passaged every 10 - 14 days as small fragments at a 1:3 to 1:4 split ratio, and can be maintained for a minimum of 10 passages while still maintaining multilineage potential and a normal karyotype. These results demonstrate that MammoCult™ Organoid Growth Medium (Mouse) efficiently generates and expands mammary epithelial cell-derived organoids and offers researchers a novel tool for in vitro mammary studies. Citation Format: David Rowbotham, Samantha Rothwell, Allen C. Eaves, Sharon A. Louis, John Stingl. Expansion of mouse mammary epithelial stem cells in serum-free organoid growth medium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6018.
Abstract 662: Late CTLA-4 Ig treatment improves antitumor efficacy of immunotherapy
Authors: Stephen Mok, James P. Allison
Journal: Cancer Research (2022)

Abstract The promising approach of combining immune checkpoint therapies such as anti-CTLA-4 and anti-PD-1 increases antitumor response and overall survival rate relative to single treatments. However, it also increases the frequency and severity of immune-related adverse events (irAEs), such as cardiotoxicity. Our previous results showed that CTLA-4 Ig (abatacept), an inhibitor of T cell costimulation through CD28, can reverse those irAEs in patients with cancer, however, its effect on the antitumor response remains unclear. In the B16F10 melanoma model, we injected mice with CTLA-4 Ig antibody when: 1) mice were first treated with anti-CTLA-4, anti-PD-1, or combination (early time point) and 2) the immunotherapy was finished (late time point). We demonstrated that CTLA-4 Ig at the early time point compromised the antitumor efficacy of the immunotherapy. In contrast, the antitumor efficacy of the immunotherapy was improved if mice were treated with CTLA-4 Ig at the late time point. We also found that the antitumor response induced by CTLA-4 Ig (late) was dependent on CD80/86. Interestingly, the frequency of ICOS+ Foxp3+ Tregs was significantly reduced by CTLA-4 Ig at the late time point. Thus, we treated B16F10 tumors in Foxp3DTR mice with anti-CTLA-4 and then with CTLA-4 Ig (late). The antitumor tumor efficacy was similar between mice treated with or without Diphtheria toxin (DT) at the late time point. This suggests that the improved antitumor efficacy of CTLA-4 Ig at the late time point was Treg dependent. Collectively, we show that CTLA-4 Ig treatment has a differential role throughout the time course of immunotherapy treatments, and this work suggests a potential combination treatment strategy with checkpoint blockade and late CTLA-4 Ig treatment. Citation Format: Stephen Mok, James P. Allison. Late CTLA-4 Ig treatment improves antitumor efficacy of immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 662.
Abstract 4216: Tipifarnib inhibits the secretion of tumor-derived small extracellular vesicles and enhances the immunotherapeutic efficacy of dinutuximab in neuroblastoma
Authors: Xiaoming Liu, Carson A. Wills, Longgui Chen, Jiawen Zhang, Yuanjun Zhao, Mi Zhou, Jeffrey M. Sundstrom, Todd D. Schell, Vladimir S. Spiegelman, Megan M. Young, Hong-Gang Wang
Journal: Cancer Research (2022)

Abstract Anti-GD2 monoclonal antibody (Dinutuximab) immunotherapy has significantly improved the overall survival rate for high-risk neuroblastoma patients. However, 40% of patients fail to respond or develop resistance to the treatment, and the molecular mechanisms by which this occurs remain poorly understood. Here we utilize the syngeneic 9464D-GD2 mouse model to investigate the role of neuroblastoma tumor-derived small extracellular vesicles (sEVs) in developing resistance to the anti-GD2 monoclonal antibody Dinutuximab. Neuroblastoma-derived sEVs significantly attenuated the efficacy of Dinutuximab treatment in vivo. Mechanistically, both RNA-sequencing and flow cytometry analysis of whole tumors demonstrated that neuroblastoma-derived sEVs modulate immune cells tumor infiltration upon Dinutuximab treatment to create an immunosuppressive tumor microenvironment, which contains more tumor-associated macrophages (TAMs) and fewer tumor-infiltrating NK cells, in addition to suppression of splenic NK cell maturation in vivo. Moreover, neuroblastoma-derived sEVs suppressed Dinutuximab-mediated NK cell antibody-dependent cellular cytotoxicity in vitro. Importantly, Tipifarnib, a farnesyltransferase inhibitor that inhibits sEV secretion, drastically enhanced the efficacy of Dinutuximab in vivo and reversed the immunosuppressive effects of neuroblastoma-derived sEVs. Notably, Tipifarnib modulated immature myeloid cells in the bone marrow to disfavor the formation of CD11b+Ly6ChighLy6Glow subpopulations, which are the precursors for TAMs. Taken together, these preclinical findings uncover a novel mechanism by which neuroblastoma-derived sEVs modulate the immune system to promote resistance to Dinutuximab and suggest that Tipifarnib-mediated inhibition of sEV secretion may serve as a viable treatment strategy to improve immunotherapy in high-risk patients. Citation Format: Xiaoming Liu, Carson A. Wills, Longgui Chen, Jiawen Zhang, Yuanjun Zhao, Mi Zhou, Jeffrey M. Sundstrom, Todd D. Schell, Vladimir S. Spiegelman, Megan M. Young, Hong-Gang Wang. Tipifarnib inhibits the secretion of tumor-derived small extracellular vesicles and enhances the immunotherapeutic efficacy of dinutuximab in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4216.
Abstract 3545: New hybrid molecular modalities comprised of DNA-origami and interfering peptides as inhibitors of protein-protein interactions
Authors: Jessica Roman, Rachel Carter, Alessandra Luchini, Lance Liotta, Remi Veneziano, Amanda Haymond
Journal: Cancer Research (2022)

Abstract Immunotherapy has shown tremendous promise in the treatment of blood cancers; however, treatment typically fails when attempted with solid tumors, such as breast cancer. However, the cases where immunotherapies have been successful in breast cancer, the results have been remarkable: full remission of stage 4 disease has been observed. This highlights the need to elucidate how the tumor microenvironment (TME) fosters a context of molecular crosstalk that is hostile to inflammatory, anti-tumor immunological responses that present a significant roadblock to consistently successful immunotherapy. Aberrant IL-33 present in the TME is believed to be one of these major factors that drives tumor progression via its ligand, ST2, and the subsequent recruitment of IL1RAcP. This activates MyD88 cascades in dysfunctional myeloid immune cells and myeloid derived suppressor cells (MDSCs), eliciting immunosuppression that promotes tumor tolerance and subsequent disease progression. To this end, preventing IL-33/ST2 signaling activation is an attractive target to possibly manipulate immune cells to recognize and mount a response against tumor cells. Our previous work has identified 4 IL1RAcP hotspot residues of interaction between it and the ST2/IL-33 complex: R157, K238, K343, and K346. Here, we designed peptides, which mimic these hotspots and the adjacent residues that interact with the ST2/IL-33 complex. Wild type peptides inhibit trimer formation in vitro as determined by immunoprecipitation and chemical crosslinking experiments. Modifications introduced to increase rigidity and stability increased affinity in vitro and showed inhibition of downstream signaling in reporter gene cell models. Citation Format: Jessica Roman, Rachel Carter, Alessandra Luchini, Lance Liotta, Remi Veneziano, Amanda Haymond. New hybrid molecular modalities comprised of DNA-origami and interfering peptides as inhibitors of protein-protein interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3545.
The Prognostic Value of CAC Zero Among Individuals Presenting With Chest Pain
Authors: Ali M. Agha, Justin Pacor, Gowtham R. Grandhi, Reed Mszar, Safi U. Khan, Roosha Parikh, Tanushree Agrawal, Jeremy Burt, Ron Blankstein, Michael J. Blaha, Leslee J. Shaw, Mouaz H. Al-Mallah, Alexandria Brackett, Miguel Cainzos-Achirica, Edward J. Miller, Khurram Nasir
Journal: JACC. Cardiovascular imaging (2022)
Abstract 518: Association of CC chemokines with breast cancer disparity
Authors: Hina Mir, Briana A. Brock, Rajeev Samant, Shailesh Singh
Journal: Cancer Research (2022)

Abstract Despite recent advances, breast cancer (BrCa) still affects many women, and the impact is disproportional in African Americans (AA) and European Americans (EA). Addressing socioeconomic and behavioral status has not been enough to reduce disparity, suggesting racial difference in BrCa biology. Our laboratory was the first to show the involvement of CC chemokines in BrCa. In this study, using ONCOMINE, TCGA, bc-GenExMiner, KMplotter, and antibody microarray, we examined the association of CC chemokines in BrCa outcomes and disparity. We show over-expression of CCL5, CCL7, CCL11, CCL17, CCL20, CCL22, and CCL25 in BrCa tissues. High mRNA levels of CCL7, CCL8, CCL17, CCL20, and CCL25 predicted a decrease in overall survival (OS). CCL7 and CCL8 were associated with decreased relapse-free survival. Expression of CCL17 and CCL25 was associated with decreased OS in AA. In EA, CCL8 was associated with decreased OS. Expression of CCL5, CCL7, CLC8, CCL17, CCL20, and CCL25 was highest in TNBC. The expression of CCL11 and CCL22 was associated with HER2 expression. CCL7, CCL8, CCL17, CCL20, and CCL25 were elevated in AAs. Since CCL25 showed a significant association with decreased OS in AA, we examined the expression of CCR9, which is the only receptor for CCL25, and CCR9-mediated signaling in BrCa cell lines derived from AA and EA. Our data show higher expression of CCR9 in AA than EA and distinct molecular cascade in cells derived from AA than EA. Furthermore, higher CCR9 expressing cells showed poor response to Carboplatin upon CCR9 activation. In conclusion, our data suggest the association of distinct CC-chemokines in BrCa progression, OS, and disparate disease outcome in AA compared to EA patients implying CCR9 signaling to be a potential target for improving chemotherapeutic response. Citation Format: Hina Mir, Briana A. Brock, Rajeev Samant, Shailesh Singh. Association of CC chemokines with breast cancer disparity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 518.